<b><i>Introduction:</i></b> Non-melanoma skin cancer (NMSC) is a cause of significant morbidity and mortality in high-risk individuals. Total body photography (TBP) is currently used to monitor melanocytic lesions in patients with high risk for melanoma. The authors examined if three-dimensional (3D)-TBP could be useful for diagnosis of NMSC. <b><i>Methods:</i></b> Patients (<i>n</i> = 129; 52 female, 77 male) with lesions suspicious for NMSC who had not yet had a biopsy underwent clinical examination followed by examination of each lesion with 3D-TBP Vectra^®WB360 (Canfield Scientific, Parsippany, NJ, USA) and dermoscopy. <b><i>Results:</i></b> The 129 patients had a total of 182 lesions. Histological examination was performed for 158 lesions; the diagnoses included basal cell carcinoma (BCC; <i>n</i> = 107), squamous cell carcinoma (SCC; <i>n</i> = 27), in-situ SCC (<i>n</i> = 15). Lesions were located in the head/neck region (<i>n</i> = 138), trunk (<i>n</i> = 21), and limbs (<i>n</i> = 23). Of the 182 lesions examined, 12 were not visible on 3D-TBP; reasons for not being visible included location under hair and on septal of nose. Two lesions appeared only as erythema in 3D-TBP but were clearly identifiable on conventional photographs. Sensitivity of 3D-TBP was lower than that of dermoscopy for BCC (73% vs. 79%, <i>p</i> = 0.327), higher for SCC (81% vs. 74%, <i>p</i> = 0.727), and lower for in-situ SCC (0% vs. 33%, <i>p</i> = 125). Specificity of 3D-TBP was lower than that of dermoscopy for BCC (77% vs. 82%, 0.581), lower for SCC (75% vs. 84%, <i>p</i> = 0.063), and higher for in-situ SCC (97% vs. 94%, <i>p</i> = 0.344). Diagnostic accuracy of 3D-TBP was lower than that of dermoscopy for BCC (75% vs. 80%), lower for SCC (76% vs. 82%), and lower for in-situ SCC (88% vs. 89%). Lesion location was not associated with diagnostic confidence in dermoscopy (<i>p</i> = 0.152) or 3D-TBP (<i>p</i> = 0.353). If only lesions with high confidence were included in the calculation, diagnostic accuracy increased for BCC (<i>n</i> = 27; sensitivity 85%, specificity 85%, diagnostic accuracy 85%), SCC (<i>n</i> = 10; sensitivity 90%, specificity 80%, diagnostic accuracy 83%), and for in-situ SCC (<i>n</i> = 2; sensitivity 0%, specificity 100%, diagnostic accuracy 95%). <b><i>Conclusion:</i></b> Diagnostic accuracy appears to be slightly lower for 3D-TBP in comparison to dermoscopy. However, there is no statistically significant difference in the sensitivity and specificity of 3D-TBP and dermoscopy for NMSC. Diagnostic accuracy increases, if only lesions with high confidence are included in the calculation. Further studies are necessary to determine if 3D-TBP can improve management of NMSC.